Astrocytic ceramide as possible indicator of neuroinflammation

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Publication

frontotemporal lobar dementia (FTLD) are characterized by progressive neuronal loss but differ in their underlying
pathological mechanisms. However, neuroinflammation is commonly observed within these different forms of dementia.
Recently, it has been suggested that an altered sphingolipid metabolism may contribute to the pathogenesis of a variety of
neurodegenerative conditions. Especially ceramide, the precursor of all complex sphingolipids, is thought to be associated
with pro-apoptotic cellular processes, thereby propagating neurodegeneration and neuroinflammation, although it remains
unclear to what extent. The current pathological study therefore investigates whether increased levels of ceramide are
associated with the degree of neuroinflammation in various neurodegenerative disorders.
Methods: Immunohistochemistry was performed on human post-mortem tissue of PDD and FTLD Pick’s disease cases,
which are well-characterized cases of dementia subtypes differing in their neuroinflammatory status, to assess the expression
and localization of ceramide, acid sphingomyelinase, and ceramide synthase 2 and 5. In addition, we determined the
concentration of sphingosine, sphingosine-1-phosphate (S1P), and ceramide species differing in their chain-length in brain
homogenates of the post-mortem tissue using HPLC-MS/MS.
Results: Our immunohistochemical analysis reveals that neuroinflammation is associated with increased ceramide levels in
astrocytes in FTLD Pick’s disease. Moreover, the observed increase in ceramide in astrocytes correlates with the expression
of ceramide synthase 5. In addition, HPLC-MS/MS analysis shows a shift in ceramide species under neuroinflammatory
conditions, favoring pro-apoptotic ceramide.
Conclusions: Together, these findings suggest that detected increased levels of pro-apoptotic ceramide might be a
common denominator of neuroinflammation in different neurodegenerative diseases.